Incidence and severity of many non-infectious and infectious diseases and vaccination efficacy differ between men and women. Although these effects could reflect sex (the biological differences between male and female) or gender (cultural norms associated with being male or female), a large body of evidence supports that these differences have a biological component. Tuberculosis (TB), a bacterial infectious disease that is one of the top ten causes of death worldwide, exhibits sex dimorphism. TB is more frequent and severe in men than women; human and murine studies demonstrate a biological component of the epidemiologically observed sex dimorphism. The present proposal stems from our surprising observation that human macrophages differentiated from monocytes ex vivo in absence of autologous serum exhibit sex bias in M. tuberculosis infection control. Sex bias was also observed in the accumulation of lipid droplets, a feature associated with decreased antimycobacterial macrophage activity that is regulated by mechanistic target of rapamycin complex 1 (mTORC1) signaling. The present proposal will determine whether sex hormones determine control of M. tuberculosis infection by inducing epigenetic reprogramming in monocytes/macrophages and involving mTORC1 signaling. The experimental plan stems from considerations derived from our preliminary results and the literature. First, the absence of autologus serum, and therefore endogenous sex hormones, in the above- mentioned experiments is consistent with the involvement of memory innate responses in the observed sex bias. Second, memory innate responses, which protect against TB, are epigenetically regulated. Third, mTORC1 signaling is regulated by sex hormones and also epigenetically. The clinical capacity and expertise at Rutgers University will provide access to populations that represent a diverse sex steroid hormone milieu: (a) cis-gender women taking hormonal contraceptives and women enrolled during and after pregnancy at the Rutgers NJMS OB/GYN clinic; and (b) transgender men and women at the Rutgers Center for Transgender Health. We have articulated this proposal in two aims. We will leverage variations of plasma levels of sex steroid hormones due to exogenous administration (Aim 1A) and pregnancy (Aim 1B) to determine relationships between hormonal levels, epigenetic profiles in immune cells, and control of M. tuberculosis infection. In Aim 2, we will determine whether the sex bias we observe in the macrophage control of M. tuberculosis infection is mTORC1-dependent. The results of the proposed work will guide interventional strategies against TB with respect to sex, pregnancy, and sex steroid hormonal therapy. Moreover, the fundamental and translational implications of the plan are generalizable to sex bias in many other diseases.